Polymorphs crystallization methods

The solid-state properties like crystallinity, polymorphism (crystal structure), shape (morphology), and particle size of drugs are important in the stability, dissolution, and processibility of drugs. Some commonly used methods in solid-state studies include microscopy, hot stage microscopy with polarized light, x-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infrared FTIR/Raman, and solid-state NMR. 

Tabic l.l gives those crystal data for the C,S polymorphs that have been obtained using single crystal methods. The literature contains additional unit cell data, based only on powder diffraction evidence. Some of these may be equivalent to ones in Table 1.1, since the unit ceil of a monoclinic or triclinic crystal can be defined in different ways, but some are certainly incorrect. Because only the stronger reflections are recorded, and for other reasons, it is not possible to determine the unit cells of these complex structures reliably by powder methods. The unit cells of the T, Mj and R forms are superficially somewhat different, but all three are geometrically related transformation matrices have been given (12,HI). 

At the empirical end of the spectrum of methods employed for the theoret-ical/computational generation of possible polymorphic crystal structures is the approach taken by Gavezzotti (1991, 1994a, 1996, 1997) and co-workers (1995,... 

Questions on the transferability of crystallization microtechniques to larger scale processes that are reproducible require careful consideration and study of crystallization kinetics. While operationally useful variables that describe crystallization methods are often related to crystallization outcomes, this approach lacks meaningful information for developing a process that yields reliable outcomes because the factors that determine the crystallization kinetics and outcomes are not explicitly considered. For instance, compare the following two approaches to describe the processes for the selective crystallization of polymorphs ... 

The salmeterol xinafoate (SX) polymorphs I and II are probably among the very few SFC-processed drug materials that have been intensively characterized. On an industrial scale, SX is produced as polymorph I in a granulated form by adding a hot solution of the drug in 2-propanol to a chilled quench solvent (48). The granulated SX material (GSX) is then subjected to micronization to yield the micronized form (MSX) for subsequent formulation work. While SX form I can be readily obtained by conventional crystallization methods, production of form II has thus far been... 

It should be stressed, that a successful analysis of solvated crystal forms requires additional methods besides those mentioned with true polymorphs. Such methods are, for example, thermogravimetry or Karl-Fischer titration and moisture sorption/desorption analysis for hydrates. In order to perform studies... 

The identification, structural and thermal characterization of new polymorphs is an important topic in solid-state chemistry and requires a battery of techniques that includes X-ray diffraction and spectroscopic methods, in addition to thermal analysis methods and dissolution techniques to determine solubility trends. Such studies are described by Caira in Chapter 16, as well as more recent theoretical techniques aimed at the prediction of the crystal structures of new polymorphs. Crystal polymorphism is particularly important in pharmaceutical products, so there is an emphasis on this area. Systems displaying solvatomorphism (the ability of a substance to exist in two or more crystalline phases arising from differences in their solvation states) molecular inclusion and isostructurality (the inverse of polymorphism) are also given due attention in this chapter. 

As described in the previous sections, the choice of crystallization method is crucial to what form is produced. Therefore it is important to perform crystallization experiments using a variety of methods to obtain a comprehensive knowledge of the polymorphic behavior of a substance. Recently developed crystallization techniques such as laser-induced crystallization, polymer-induced heteronucleation, crystalUzation from supercritical fluids, capillary growth, and HTS have been shown to be useful in exploring the solid-form diversity. In this section, we describe a few crystallization techniques that are being used to grow new polymorphs. 

Classical crystallization methods have been reviewed by Guillory [18] and are listed in Table 5.2. Depending on the method, various degrees of freedom are possible. They include type of solvent or solvent mixture, cooling profile, temperature at start, temperature at end, concentration, pressure, humidity, surface-to-volume ratio, vessel type, and material of surface. Furthermore, many crystallization experiments are influenced by the initial solid-state form that is used (i.e., polymorph, solvate, hydrate, or the amorphous form) as this can affect the solubility and hence the degree of supersaturation. 

Real polymorphic inclusion crystals, which consist of not only identical host-to-guest ratios but also different hydrogen-bonded networks, were found by two groups. The one deals with the crystals of deuterated urea (ND2COND2) with sebaconitrile [1], and the other deals with those of cholic acid(l) (Fig. 1) with acrylonitrile [2]. It is empirically known that selective acquisition of any desirable crystal from multiple polymorphic crystals on the basis of recrystallization accompanies poor reproducibility [3]. In fact, we happened to obtain the latter crystals by addition of a third component. But now, we can surely and selectively acquire the crystals in the presence of different kinds of butanols under definite temperatures and concentrations. This method led us to the finding of another polymorphic crystals of 1 with methacrylonitrile having different hydrogen-bonded networks from those of 1 with acrylonitrile. 

The inclusion crystals of 1 are usually produced by direct recrystallization from liquid guests (Method A) [4] and/or by using some solvents (Method B) [5]. In the case of acrylonitrile [2], Methods A and B gave the crystals with a crossing structure [6] and a bilayered structure [7], respectively. Method B enables us to control the recrystallization conditions as compared to Method A. Four different items were applied to Method B as mentioned below, leading to selective acquisition of the polymorphic crystals. 

Another example in the literature on the preparation of pure polymorphic forms of drug compounds by SCF processing is that of fluticasone propionate, which is also a drug delivered by the respiratory route (27). As the compound decomposes before melting, DSC traces do not give definitive temperature profiles for the transformation between polymorphs I and II. X-ray diffraction patterns, however, have been used to confirm the presence of different polymorphic forms. The drug recrystallizes as form II from solution by the SEDS process in the presence of supercritical carbon dioxide at all temperatures, while form I is obtained by conventional crystallization methods. The rapid nucleation by SCF antisolvent aids in the formation of the metastable form II. A further advantage of SCF... 

Since crystalline compounds sometimes show polymorphism depending on the crystallization method, i.e., whether vapor phase or liquid phase, on the growing rate of crystals, and on the solvent used for recrystallization, proper selection of the crystallization conditions is necessary. For example, 4-pyrrolidino-3-(A-(acetyl)amino)nitrobenzene (PAN) was found to give SHG-active crystals by rapid recrystallization and SHG-inactive crystals by slow growth of crystals. ... 

Since the physical properties of semicrystalline polymers usually depend on crystal modification, the study of the effects of crystallization and processing conditions on the polymorphic behavior is essential to tailor the performance of polymeric materials. Aside from T, crystallization methods (e.g., melt, cold, or solution crystallization), and stress, crystal modifications of polymers can be regulated by many other factors. 

Maginn and Jayaraman computed the melting point of two polymorph crystals of the IL [bmim][Cl] using a thermodynamic integration-based atomistic simulation method [46] (The absolute errors were in the range of 30 to 50 °C).[47]... 

Parrinello M and Rahman A 1981 Polymorphic transitions In single crystals a new molecular dynamics method J. Appl. Phys. 52 7182-90... 

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